PubMed · 2717106
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C Mansell. 1989-05-10. Acyclovir resistance.. https://pubmed.ncbi.nlm.nih.gov/2717106/
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Nineteen cases of human immunodeficiency virus (HIV)-associated oral hairy leukoplakia (HLP) and Epstein-Barr virus (EBV) replication were treated with high-dose oral valacyclovir to inhibit productive EBV replication. The clinical, histopathological, and molecular viral responses to treatment were assessed in surgical biopsy specimens obtained before, during, and after treatment. In the majority of treated cases, HLP was resolved, and EBV replication was terminated. In many cases, the initial response to inhibition of replication was a persistent, nonproductive, EBV infection of the oral mucosa, characterized by limited expression of replicative EBV genes, especially BZLF1. In some cases, productive EBV replication recurred after discontinuation of treatment with valacyclovir. In a few treated cases, treatment failed, and productive EBV replication persisted, possibly because of the evolution of acyclovir-resistant EBV. In summary, safe treatment of HLP and of EBV replication, with valacyclovir, provides new insight into the mechanisms of EBV persistence in oral mucosa.
In human, purine nucleoside phosphorylase (HsPNP) is responsible for degradation of deoxyguanosine and genetic deficiency of this enzyme leads to profound T-cell mediated immunosuppression. PNP is therefore a target for inhibitor development aiming at T-cell immune response modulation and has been submitted to extensive structure-based drug design. This work reports the first crystallographic study of human PNP complexed with acyclovir (HsPNP:Acy). Acyclovir is a potent clinically useful inhibitor of replicant herpes simplex virus that also inhibits human PNP but with a relatively lower inhibitory activity (K(i)=90 microM). Analysis of the structural differences among the HsPNP:Acy complex, PNP apoenzyme, and HsPNP:Immucillin-H provides explanation for inhibitor binding, refines the purine-binding site, and can be used for future inhibitor design.
PURPOSE: The main reasons for graft failure following penetrating keratoplasty in patients with herpetic eye disease are recurrence of herpetic disease and allograft rejection. In a randomised trial the effect of systemic acyclovir and mycophenolate mofetil (MMF) on these post-keratoplasty complications was evaluated. PATIENTS AND METHODS: Patients with typical clinical findings of recurrent herpetic keratitis were enrolled in this single-centre study after contraindications to systemic immunosuppression were ruled out. In a prospective randomised trial 30 patients were treated in three groups. In group A patients received acyclovir 200 mg five times/day for 3 weeks. In group B patients were treated with acyclovir 200 mg five times/day for 1 year, and patients in group C received acyclovir 200 mg five times/day in combination with MMF 1 g twice daily for 1 year. RESULTS: In group A 3 patients experienced seven herpes recurrences. One patient had a moderate and one further patient a severe allograft rejection. In group B three severe allograft rejections were observed. Herpes recurrences did not occur while receiving acyclovir prophylaxis, but only once after the prophylaxis had been stopped. In group C no herpes recurrence was observed, and only two mild allograft rejections occurred while being under combined acyclovir-MMF therapy. Another mild and one moderate allograft rejection were observed after cessation of MMF. CONCLUSIONS: These results demonstrate that systemic acyclovir protects the grafts from recurrences of herpetic disease as long as it is administered at efficient doses. Simultaneously administered mycophenolate mofetil does not trigger herpes recurrences and protects the graft from severe allograft rejections, but mild, less dangerous immune reactions may still occur while receiving MMF. The combination of systemic acyclovir and mycophenolate mofetil therefore is recommended for patients at high risk for herpes recurrence and allograft rejections.